Ethylbenzyl, lauryl, dimethyl ammonium salts



CHEM? Patented Apr. 27, 1954 ETHYLBENZYL, LAURYL, DIlVIETHYL AMMONIUM SALTS Reginald L. Wakemaii and Giuliana C. Tesoro,

Brooklyn, N. Y., assignors to Onyx Oil & Chemical Company, Jersey City, N. J., a corporation of New Jersey No Drawing. Application February 15, 1950, Serial No. 144,378

2 Claims. 1

This invention relates to antimicrobial substances and specifically to quaternary ammonium compounds that show high antimicrobial activity.

The antimicrobial activity of quaternary ammonium compounds has been known for sometime, as is evidenced by U. S. Patent No. 2,108,765, granted February 15, 1938, to Domagk. These compounds have come into fairly wide use as antiseptic agents, but unfortunately, commercially available compounds do not exhibit an activity as high as is known to be obtainable.

Thus Lawrence et al. have reported, in an article in the Journal of the American Pharmaceutical Association, volume 36, No. 51, pages 353 to 358 (November 1947), the phenol coefiicients of several (alkyl, benzyl, dimethyl) ammonium chlorides as follows:

Phenol coefiicz'ents of alkyl dimethyl benzyl ammonium chlorides It is accordingly clear that quaternary ammonium compounds could be made to have the high activity shown by Lawrence et al. for the (tetradecyl, benzyl, dimethyl) ammonium chloride if the tetradecyl radical could be readily incorporated at a reasonable cost. However, this radical is most readily provided by myristic acid, which occurs only in small quantities in some relatively scarce fats and oils and is therefore not easily available in commercial quantities. For this reason the most Widely used prior commercial quaternary antimicrobial compound has been the dodecyl, benzyl, dimethyl, ammonium chloride referred to by Lawrence et al., the dodecyl radical being readily available commercially from lauric acid which is found in large quantities in coconut oil. In actual manufacture the prior art preparation is somewhat more effective than indicated in the Lawrence et al. article. This is apparently because natural lauric acid normally contains appreciable quantities of 14-, and lS-carbon acids in addition to the 12-carbon acid, and the natural acid is used without separation of these materials. In general about a 50% increase in phenol coeiiicient can be contributed by this factor.

Among the objects of the present invention is the provision of improved commercially attractive quaternary ammonium compounds having higher antimicrobial activity than the commercial preparations heretofore available.

An additional object of the present invention is the provision of highly efiective antimicrobial quaternaryammonium compounds that contain no aliphatic carbon chain longer than 13 carbons in any straight length. x

A further object of the present invention is the provision of new antimicrobial quaternary ammonium compounds which have only one long carbon chain with 10 or 12 carbon atoms.

Still further objects of the present invention will be more readily understood from the following description of exemplifications thereof.

It has been discovered that antimicrobial activities approximating or exceeding the maximum shown by Lawrence et al., can be readily provided in commercially feasible quaternary benzyl, dimethyl, ammonium compounds having additional aliphatic su'bstituents, none of which have as much as 14 carbons in any one straight chain, and the totalnumber of carbon atoms in all these additional substituents is between 13 and 16. In a more limited sense the new compounds of high antimicrobial activity have the quaternary ammonium radical:

where A represents at least one aliphatic sub-- stituent, R represents at least one aliphatic substituent, all of these aliphatic substituents have less than 13 carbon atoms in any one straight chain, and the total number of carbon atoms in all these substituents is between 12 and 15.

More specifically the compounds of the invention have a quaternary ammonium radical:

where A represents at least one aliphatic substituent, R represents an aliphatic substituent having at least 8 and no more than 12 carbon atoms, and the total number of carbon atoms in all these substituents is between 13 and 16.

In a still more restricted sense high antimicrobial activity has been found in (alkyl, benzyl, dimethyl) ammonium compounds where the alkyl radical is a lauryl or decyl group and the benzy-l radical has at least one aromatically bound aliphatic group, which together with-the alkyl radical have a total number of between 13 and 16 carbon atoms.

The present discovery shows :that the antimicrobial activity of (alkyl, benzyl, dimethyl) 1ammonium compounds, where the alkyl radical has less than 14 carbon atoms, can be greatly vincreased by the substitution of at "least onetaliphatic group in the benzene ring of the benzyl radical. The following are typical phenol-coefficients of the compounds of the invention with respect to Staphylococcus aureusand Salmonella typhosa:

S. aureus S. typhosa l. (Ar-inethyl-benzyl, lauryl, dimethyl) ammonium chloride 466 300 2. (Ar-ethyl-benzyl, lauryl, dimethyl).

ammonium chloride 766 600 3. (Ar-dimethyl-benzyl, lauryl, dimethyl) ammonium chloride (isomeric mixture of dimethyl benzyls) 500 620 i. (2,4'diinothyl-bcnzyl, lauryl, dimethyl) ammonium chloride 666 500 5. (3,4-dimethyl-benzyl, lauryl, dimethyl) ammonium chloride 760 500 6. Mixed (Ar-triand (Antetra-methylbenzyl, lauryl, dimethyl) ammonium chloride 466 A 7. (Ar-chlor, Ar-metbyl-benzy, lauryl, di-

methyl) ammonium chloride 583 412 8. (Ar-socondary-butyl-benzyl, lauryl, di-

methyl) ammonium chloride 533 412 9. (Arsccondarybutyl-benzy1, decyl, (ll- Inetnyl) ammonium chloride 667 413 In each case the phenol coefficient was determined at 20 C. by the standard method-given in the United States Department of. Agriculture, Circular No. 198.

The results are rather surprising :in view of the fact that neither the physiological nor. physical characteristics of a single long aliphatic chain has heretofore been considered'ascapable of being duplicated by any number of smaller chains, particularly by smaller chains that when put together are no longer than the long chain sought to be duplicated.

Furthermore, the benzene ring is the last place that would be considered suitable for the attachment of a short aliphatic group in an attempt to provide the characteristics of a long chain and thereby more closely duplicate the effect of the tetradecyl group which is directly attached to the quaternary nitrogen atom. It is found, however, that any (Ar-methyl-benzyl, lauryl, dimethyl) compound is about two times as active as the (benzyl, lauryl, dimethyl) compound, as measured by the respective phenol coeflicients, and the corresponding (Ar-dimethylbenzyl, lauryl, dimethyl) compound is even'more active.

The present invention also encompasses halogen substituted derivatives of the above compounds. It has been found that the replacement of one or more of the hydrogens in any of the above compounds does not significantly impair its antimicrobial activity, and in some cases materially improves it. Thus, as shown above the substitution ot a chlorine for a benzene ring hydrogen in (Ar-methyl-benzyl, lauryl, dimethyl) ammonium chloride increases itsphenol .coeflicient about one-third. The corresponding bromo and iodo compounds show even higher phenol coefficients. Substitution of fluorine generally results in a slight impairment in activity.

The improved compounds of the invention have been prepared as follows:

(Ar-ethyZ-beneyl, lauryl, dimethyl) ammonium chloride Thirty-eight grams (0.25 mol) of Ar-ethylbenzyl chloride (an isomeric mixture prepared by chloromethylating ethyl-benzene) and 61 grams (0.25 mol) .of lauryl dimethyl amine were mixed and heated with mechanical stirring until the reaction becameexothermic. The temperature was then maintained at -l00 C. for 30 minutes or until the mixture became too stiff to stir. One hundred and twenty-five grams of cold water were then added, and the mixture was heated with stirring at C. until the clear solution formed reached the calculated ionizable chloride content (3.9% Cl for a 44% solution indicating 100% reaction). Twenty-six grams of water were then distilled ofi" to remove unreacted organic material and to give a clear, pale yellow 50% solution containing 4.4% chloride.

The compound thus prepared exhibits the phenol coefiicients already listed in Example 2 of the preceding table. Another method of evalvuating the merit of a germicide is to determine the time required for a given concentration to kill 99.99999% of the number of microorganisms present in the original inoculum. Using the preparation of this example in distilled water, it has been found by plate counts that this percentage of kill with respect to the tested strain of Eseherichia coli is attained at a concentration of 78 parts per million after 30 seconds, whereas a .concentration of parts per million of a commercial sample of (lauryl, dimethyl, benzyl) ammonium chloride was necessary to achieve the sameresults after 60 seconds.

The other compounds have been prepared in the same manner using the appropriately modified benzyl chloride and alkyl dimethyl amine. Readily available mixtures of isomeric benzyl compounds were used except in the preparation of the compounds of Examples 4 and 5 above.

The compounds of the invention can be prepared by processes other than that described above. One such alternative technique is to mix at a temperature of about 100 C. a lauryl or decyl halide (bromides and chlorides are highly effective) with a suitable tertiary benzyl amine.

When purified dodecyl compounds are used in place of the natural lauryl mixture, the quaternary products show about the same or slightly higher activity. Apparently the presence of a 14-carbon alkyl chain in the quaternary compounds of the invention does not contribute any aqueous solutions of these materials is not feasible by reason of the fact that even heating is impossible and the solutions tend to bump or suddenly liberate vapor with considerable violence, usually causing liquid, to be'shot outwith the vapors. The quaternizing reactions do not go to completion in the absence of solvent because of mechanical difiiculties.

High concentrations (90% or over) of the new quaternary compounds can be prepared by carrying out the quaternizing in relatively volatile solvents such as absolute alcohol or acetone, and then evaporating off the solvent. Such 90% preparations are clear, pale yellow, extremely viscous syrups, which tend to form skins on their surface upon standing in a desiccator. The syrups are extremely soluble in Water, ethanol, isopropanol, acetone, benzene, ethyl ether and ethyl acetate, although practically insoluble in petroleum ether. With dilute aqueous solutions of sodium picrate they react to form water-insoluble yellow oils.

The 90 by weight (Ar-ethyl-benzyl, lauryl, dimethyl) ammonium chloride (the balance being essentially Water) has a specific gravity of 0.936 at 30 C. with respect to Water at the same temperature. Its index of refraction for the yellow sodium lines at 25 C. is 1.495. The syrups of the other compounds have correspondin values.

The new compounds can be prepared in dry form on a suitable carrier, such as urea, to yield free-flowing powders containing at least 20% of the quaternary compound by weight.

By reason of the cationic surface acivity of the quaternary compounds of the invention, they are also highly effective as wetting, dispersing or froth flotation agents. They may be utilized as textile finishing agents to impart softness, for example, to the treated goods. Applied to Woolen fabrics, they also exhibit valuable moth-proofing characteristics. They are not irritating to the skin or body nor toxic in use dilutions.

The characteristics of the new compounds include strong algicidal and fungicidal behavior as well as effective action as deo dorants.

The compounds of the invention show their strong antimicrobial properties either as the free quaternary ammonium hydroxide, or as the quaternary ammonium hydroxide salt of a hydrohalogen acid such as hydrochloric and hydrobromic acid, or a nitric acid, sulfuric acid, phosphoric acid such as orthometaand pyrophos phoric acid as well as phosphorous acids, or any of the other acids taught in Domagl: Patent No. 2,108,765, including the organic acids.

As many apparently Widely different embodiments of this invention may be made without departing from the spirit and scope hereof, it is to be understood that the invention is not limited to the specific embodiments hereof, except as defined in the appended claims.

What is claimed is:

1. An (Ar-ethyl-benzyl, lauryl, dimethyl) ammonium chloride.

2. A mineral acid salt of an (Ar-ethyl-benzyl, lauryl, dimethyl) ammonium hydroxide.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,302,805 Schussler Nov. 24, 1942 2,314,111 Tucker et a1. Mar. 16, 1943 2,395,989 Bock Mar. 5, 1946 2,416,264 MacMullen et a1. Feb. 18, 1947 2,499,213 De Benneville et a1. Feb. 28, 1950 2,569,408 De Benneville et a1. Sept. 25, i

FOREIGN PATENTS Number Country Date 217,134 Switzerland Feb. 16, 1942 458,033 Great Britain Dec. 8, 1936 499,203 Great Britain Jan. 16, 1939 782,930 France Mar. 25, 1935 

2. A MINERAL ACID SALT OF AN (AR-ETHYL-BENZYL, LAURYL, DIMETHYL AMMONIUM HYDROXIDE. 